Rapid appearance and local toxicity of amyloid-β plaques in a mouse model of Alzheimer’s disease

Abstract

The senile plaques in brains of Alzheimer's disease sufferers are thought to develop gradually over years. The involvement of plaques in the pathology of Alzheimer's disease is a hotly debated issue. New work, using mutiphoton microscopy to follow plaque formation in vivo in a mouse model of the disease, supports the view that amyloid plaques appear before local neurotoxicity is visible. Surprisingly, senile plaques form rapidly, within 24 hours: within a day or two microglial cells accumulate and neuritic abnormalities start to appear. Based on these observations, it's possible to speculate that the slow degeneration in Alzheimer's disease is marked by sudden changes in cortical structure, and that altering the kinetics of this process might change the rate of disease progression. Senile plaques are thought to accumulate over the course of decades in brains of Alzheimer's disease patients. In vivo mutiphoton microscopy is used to follow the birth of such plaques in live Alzheimer's disease model mice. It is found that plaques form extraordinarily quickly, over 24 hours. Within 1–2 days, the microglia move in and noticeable neuritic changes ensue. These data argue that neuritic dysfunction follows, rather than precedes, amyloid deposition. Senile plaques accumulate over the course of decades in the brains of patients with Alzheimer’s disease. A fundamental tenet of the amyloid hypothesis of Alzheimer’s disease is that the deposition of amyloid-β precedes and induces the neuronal abnormalities that underlie dementia1. This idea has been challenged, however, by the suggestion that alterations in axonal trafficking and morphological abnormalities precede and lead to senile plaques2. The role of microglia in accelerating or retarding these processes has been uncertain. To investigate the temporal relation between plaque formation and the changes in local neuritic architecture, we used longitudinal in vivo multiphoton microscopy to sequentially image young APPswe/PS1d9xYFP (B6C3-YFP) transgenic mice3. Here we show that plaques form extraordinarily quickly, over 24 h. Within 1–2 days of a new plaque’s appearance, microglia are activated and recruited to the site. Progressive neuritic changes ensue, leading to increasingly dysmorphic neurites over the next days to weeks. These data establish plaques as a critical mediator of neuritic pathology.